Differential Gene Expression in the Prenatal Brain of Cyclooxygenase-1 and 2 Knockout Male Mice - A Model System of Autism Spectrum Disorders

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Abstract

Prostaglandin E2 (PGE2) is an endogenous lipid-derived signalling molecule, synthesized in part by the rate-limiting enzymes Cyclooxygenase-1 and 2 (COX-1 and 2). Along with inducing inflammation, PGE2 is important for brain development, neuronal transmission, plasticity and modulation of an important developmental pathway known as the Wnt pathway. Due to its role in brain development, any genetic or environmental factors interfering with PGE2 levels may result in abnormal brain development and Autism Spectrum Disorders (ASDs). To explore the role of PGE2 in the developing brain we examine changes in the expression of genes and their associated pathways using RNA microarray analysis of mice brains lacking PGE2 producing enzymes COX-1 and 2 at embryonic days 16 and 19. We also aim to determine whether there is an interaction between PGE2 and Wnt pathways in the brain of COX-/- mice by western blot analysis of -catenin, a key signal transducer in the Wnt pathway. We also aim to quantify the expression of selected developmental and ASD candidate genes in our cellular models exposed to a higher level of PGE2. Overall, we found a greater number of differentially expressed genes, of which more were down-regulation than up-regulation, in the E16 COX-/- mice than E19 mice. In addition, several important developmental and ASD candidate genes along with their corresponding neuronal pathways, including synaptic transmission and Wnt signalling pathways, were affected, particularly in the E16 COX-2-/- mice. We also found greater Protein Kinase A (PKA) induced -catenin activation in the COX-2-/- E16 mice. PGE2 exposed neuroectodermal (NE-4C) stem cells and neuronal cells indicated changes in the expression of genes that were also differentially expressed in COX-/- microarray results. This research provides an in-depth look at the role of COX/PGE2 during prenatal brain development and the implications for the COX-/- mouse to serve a potential ASD model system.